RNA interference (RNAi) is a post-transcriptional process in which double stranded RNA (dsRNA) triggers sequence-specific suppression of homologous genes. The first evidence that dsRNA leads to post-transcriptional gene silencing in animals came from work on Caenorhabditis elegans. As reconstructed in cell extract experiments in Drosophila melanogaster and Homo sapiens, dsRNA is digested into 21-23 nucleotide (nt) fragments of small interfering RNA (siRNA) by a member of the RNase III family of ATP-dependent, dsRNA-specific ribonucleases called Dicer.
These siRNA duplexes bind to a nuclease complex to form the RNA-induced silencing complex (RISC), with the antisense strand serving as a cognate template for specific transcript recognition. RISC catalyzes cleavage of specific mRNAs, which is followed by rapid degradation by cellular exonuclease activity. Longer dsRNAs (>50 bp) have a more widespread effect in mammalian somatic cells, inducing general arrest of protein synthesis through an interferon response and protein kinase activation. Shorter siRNAs of 21-23 nt, in contrast, have a more targeted effect, inducing up to 90% depletion of specific mRNAs both in vitro and in vivo.
The ear is exquisitely sensitive, being able to detect frequencies from as low as 16 Hz to as high as 20,000 Hz. This incredible sensitivity is based in the membranous labyrinth housed in the bony cochlea, a spiral canal about 31-33 mm long winding 2½ times around a central bony modiolus. The pars inferior of the membranous labyrinth includes the human cochlea, which has 3500 inner hair cells and about 12,000 outer hair cells. The hair cells have stereocilia, about 120 stereocilia on each inner hair cell and 46-148 stereocilia on each outer hair cell.
The most obvious abnormality of inner ear function is deafness, the most common of sensory deficits. Congenital deafness, for example, affects approximately one in 1,000 children. In half of these newborns, the cause is environmental, and in half, it is genetic. With age, the burden of genetic deafness increases to such an extent that by the age of 80, 50% of the population will have hearing loss sufficient in degree to require the use of amplification. The causes of this age-related hearing loss are complex and include both genetic and environmental factors.
Over the past decade, the scientific understanding of nonsyndromic hereditary hearing loss has increased. Loci associated with autosomal dominant, autosomal recessive, x-linked, mitochondrial, and even modifier genes have been identified. Each locus is named with an appropriate prefix, for example DFNA for dominant and DFNB for recessive, followed by a suffix integer to indicate locus in order of discovery.
For many of these loci, the causally related genes have been cloned, and this knowledge has translated to clinical medicine and changed the way children and adults with presumed hereditary hearing loss are evaluated. There has been a dramatic increase in the number of requests from clinical diagnostic laboratories for genetic testing for hearing loss.